Monoclonal antibodies to myelin associated glycoprotein (MAG) in patients with sensory or mixed sensory-motor demyelinating polyneuropathies occurring in association with IgM gammopathy (paraproteinemia) are all directed toward carbohydrate epitopes in MAG and cross react with other glycoproteins of PNS myelin including PO and PMP-22, as well as with the glycosphingolipid, sulfate-3-glucuronyl paragloboside (SGPG). However, our recent results have shown that these human antibodies exhibit substantial heterogeneity among patients with regard to the relative strengths with which they bind to these potential target antigens. For example, the strengths of binding to SGPG did not correlate well with the strengths of binding to MAG or other glycoprotein antigens, and some antibodies exhibited exceptionally strong reactivity with the proteins of compact myelin, P0 and PMP-2. Whereas these glycoprotein antigens are expressed only by myelinating Schwann cells, SGPG has a wider distribution. It is also expressed in neurons and neural endothelial cells. Furthermore, we have now shown that SGPG is expressed in primary Schwann cell cultures in the absence of neurons and in two Schwann cells lines generated in our laboratory that do (S16) and do not (S16Y) express myelin markers. These findings suggest that non-myelinating Schwann cells may also be a target of anti-MAG antibodies that react strongly with SGPG. Because of the different locations of the potential target antigens, the variations from patient to patient with regard to relative strengths with which anti-MAG antibodies bind to the different antigens could affect pathogenic mechanisms and contribute to clinical variability. Other patients with neuropathy frequently have monoclonal or polyclonal antibodies to ganglioside antigens in nerve. Clinical subsets of these patients include motor neuropathy in association with antibodies to GM1 ganglioside or sensory-ataxic neuropathy (SAN) in association with antibodies to gangliosides containing disialosyl moieties such as GD1b and GT1b. Chronic inflammatory demyelinating neuropathy (CIDP) sometimes occurs in association with malignant melanoma, and it may be caused by induction of antibodies to glycolipid antigens shared between melanoma and neural antigens, both of which are of neuroectodermal origin. This hypothesis was supported by our finding of antibodies to SGPG and to GM2 ganglioside in a patient with melanoma and CIDP. Experiments are in progress using cultured neural cells and rats immunized with gangliosides as models to explore pathogenic mechanisms occurring in patients with neuropathy and anti-glycolipid antibodies.